Angiotensin II type 1 receptor antagonists for which the present invention has found a new medical use are known in the art. However, nothing has been reported or is generally known concerning the pharmacological and/or therapeutic properties of these compounds with respect to effects on dyspeptic symptoms.
In connection with the present invention an angiotensin II type 1 receptor antagonist of the general formula I is employed: ##STR1##
The compounds listed above may be used in racemic form or in the form of a substantially pure enantiomer; they may be used in neutral form or in the form of a salt, preferably a physiologically acceptable salt such as sodium, potassium, ammonium, calcium or magnesium. Where applicable the compounds listed above can be used in hydrolysable ester form.
The compound of the formula I wherein A is the I:1 moiety has the generic name losartan and is known from European patent no. 253 310.
The compound of the formula I wherein A is the I:5 moiety has the generic name candesartan cilexetil, code no. TCV-116 and is known from EP-459 136.
The compound of the formula I wherein A is the I:9 moiety is known under the generic name irbesartan.
The compound of the formula I wherein A is the I:13 moiety has the generic name candesartan and is known from EP-459 136.
Functional disorders of the gastrointestinal tract are common and account for a very large number of medical consultations. On an annual basis approximately 30% of the western population experience such dyspeptic symptoms varying from mild indigestion to severe pain. The symptomatology may be due to an organic disease (for example peptic ulcer disease) or, more commonly, be without any known origin (i.e. absence of organic pathology in the upper gut as evidenced by various diagnostic procedures). In clinical routine the latter symptom-syndrome is commonly called "non-ulcer dyspepsia", "functional dyspepsia", "non organic dyspepsia" etc. Treatment of dyspepsia of unknown origin involves a variety of pharmacological principles (i.e. neutralization of gastric acidity, drugs affecting the motility of the gut wall etc.) some of which have doubtful efficacy and sometimes with severe side effects.
Dyspepsia due to peptic ulcers can be cured by intake of antacids and inhibitors of gastric acid secretion. Ulcer-like dyspeptic symptoms without mucosal pathology are usually also sensitive to a similar treatment. This subpopulation of dyspeptic symptoms (acid related dyspepsia) is thus defined by the symptom-relief in association with intake of neutralizing agents or inhibition of gastric acid production by use of proton pump inhibitors or histamine type2-receptor antagonists. However the former principle is shortlasting and neutralizing drugs must thus be administered repeatedly during the day. The latter drugs have disadvantages of being expensive and exert a great impact on gut physiology as the antacid gastric conditions increase the risk for intestinal and/or systemic infections. Prokinetic drugs (such as cisapride) or anticholinergic compounds are other pharmaceutical principles that are utilize for dyspeptic symptoms, usually with variable effect and high frequency of side effects. It follows that available drug regimens for treating dyspeptic symptoms are impaired by serious disadvantages.
Compounds that interfere with the renin-angiotensin system (RAS) are well-known in the art and are used to treat cardiovascular diseases, particularly arterial hypertension and cardiac failure. Principally, the RAS can be interfered with by inhibition of the enzymes synthesizing angiotensins or by blocking receptors at the effector sites. Available today are renin-antagonists, inhibitors of the angiotensin converting enzyme (ACE) and angiotensinII-receptor (AII-receptor) antagonists. In addition to cardiovascular effects, some of these compounds have been claimed to exert effects on unspecified "gastrointestinal disorders".